Inhalers are commonly used to deliver drugs into the body via the lungs, typically for treating conditions such as asthma and Chronic Obstructive Pulmonary Disease (COPD).
The most common type of inhaler is the so-called metered dose inhaler (MDI) in which the drug to be delivered is stored in solution or suspension in a pressurized container that contains a propellant. In use, the MDI releases the drug in an aerosol. Another type of inhaler is the dry powdered inhaler (DPI) in which a drug in powder form is delivered to a patient. Generally, dry powder drug formulations have the advantage over solutions or suspensions in that they are usually more stable during storage and therefore offer a longer shelf life.
The use of inhalers to deliver drugs in this way has several advantages over other drug delivery methods, such as injections. In particular, inhalers enable rapid onset of relief, the drugs being delivered are not metabolised before entering the blood of a patient, and delivering drugs in this way is not painful or, indeed, even uncomfortable.
In contrast, injections where drug formulations are delivered in liquid form (either as a solution or a suspension) can be painful when administered and often require cold storage, which is particularly the case for vaccines. This is a particularly costly disadvantage when shipping vaccinations around the world, as they must be kept sufficiently cold throughout the entire journey. Sharing needles used for injections can spread infectious diseases, which is a particularly recognised problem in developing countries. So called needlestick injuries, where a health care worker administering the injection is injured by the needle from the injection are also seen as a threat posed by injections.
Because of the numerous advantages of using inhalers, and DPIs in particular, to deliver drugs fast and effectively, there is much research into developing dry powder formulations to treat therapies beyond asthma and COPD. For example, the systemic delivery of drug molecules via the pulmonary route could be used to alleviate chronic pain (such as, breakthrough cancer pain), or DPIs could be used for needleless administration of insulin for the treatment of diabetes.
Many of these drug formulations undergoing development need to be delivered in quantities much higher than the typical doses of several tens or hundreds of micrograms required for treating asthma and COPD. For this reason, there is a drive to create respirable “engineered” drug formulations, which do not use the carrier particles (usually lactose) that are typically usually used for DPIs used for treating asthma and COPD.
The majority of DPI devices currently on the market are ‘passive’ devices, which are solely reliant on the inspiratory energy of the patient to create a respirable aerosol. Passive DPIs to date have typically been developed to deliver blended dry powder formulations, which use relatively large (50 to 300 μm) lactose carrier particles to bulk up the volume of each dose (typically micrograms) of active pharmaceutical ingredient (API). This improves metering accuracy for small doses (as well as aiding powder handling during manufacture, for example, by improving the flowability of the blend). Even for higher doses, a carrier can still be beneficial, as it is extremely difficult to aerosolise pure API using only the inspiratory power from the patient.
In order for the small API particles to reach the deep lung, the aerosolization engine of the DPI must somehow detach the pure drug from the carrier particle on inhalation. Most aerosolization engines within passive DPIs use combinations of impact and shear forces to break-up, disperse and aerosolize formulations. Even the most effective passive DPIs, however, cannot ensure complete deagglomeration of drug and carrier particles on delivery, and the majority of pure drug delivered from the device (typically 70-80%) remains attached to the larger carrier particles. Rather than being delivered to the deep lung for treatment, these combined particles impact on the mouth and throat, both wasting the drug and potentially leading to unwanted side effects.
To avoid this problem with deagglomeration, it would be desirable to deliver API-only formulations of drug from a DPI. The problem with this is that while aerosolization engines including swirl chambers, cyclones and similar are effective for carrier-based formulations, they do not work well with API-only formulations, as the presence of the large carrier particles has a significant impact on the operation of the DPI. For example, without the presence of larger carrier particles API would accumulate at the walls, where it is not exposed to the aerodynamic drag caused by the airflow (as the size of respirable particles is smaller than the thickness of the boundary layer), and can be held there by a combination of Van der Waal's, electrostatic and surface energy forces. These close-acting forces can vary depending upon, for example, environmental conditions and consequently the accumulated fraction of deposition can be thought of as ‘fragile’. For example, the impact created by knocking or dropping the inhaler could dislodge the deposition (unknown to the user), who could then receive a much higher dose than expected. This would mean that the inhaler product would (rightly) fail the mandatory dose content uniformity requirements, and not be approved for regulated markets. This is a significant reason why current DPIs that use relatively large carrier particles for the API are not necessarily suitable for delivering API-only formulations.
The use of carrier particles greatly increases the costs of formulation development of drugs for use in DPIs, due to the need to create a homogeneous blend of API with the carrier excipient. Particles also have to be made smaller than necessary to account for incomplete deagglomeration by the device engine, and the stability of the carrier-API mix must be ensured. Furthermore, poor carrier-API deagglomeration means that the best passive DPIs (using a carrier) currently available are typically no more than 50% effective or, in other words, 50% of the drug (API) is wasted in normal use.
Although passive devices are low cost, their performance is typically limited by the underlying physics, and they typically require high formulation development costs. A further disadvantage of passive devices is that the delivered dose of API is highly dependent on the inhalation strength of the user, which may not be sufficient in patients who are unwell, elderly or very young.
For these reasons, the delivery of active pharmaceutical (API)-only engineered formulations, for DPI therapies beyond asthma and COPD, requires different device technology to carrier-based DPIs.
In order to meet this demand, ‘active’ dry powder inhalers capable of delivering API-only formulations are under development as an alternative to passive DPIs. Rather than relying on the inspiratory effort of the user, active DPIs provide the power to aerosolise and deliver the API by another means, leading to a uniform and repeatable drug-delivery step that is independent of the inhalation strength of a user. This power may be provided, for example, via electricity from a battery or from compressed air. Active delivery provides huge performance advantages, but existing devices are complicated to use and manufacture, and as a result are costly for both companies and patients. Due to the high complexity and expense of active DPIs, there are currently no active devices on the market.
Development is currently divided between passive devices with limited performance but a low cost, and active devices that offer high performance, but at a much higher cost. There is therefore a great demand for a device that combines the high performance of active delivery with the low cost and simplicity of passive delivery.